This research program will continue to investigate the regulation of nitric oxide (NO) synthesis in astroglial cells and the role of astrocyte- derived NO in the CNS. During the current funding period the investigators have described the transcriptional induction of a NO synthase (iNOS) in astrocytes in response to endotoxin and cytokines. Experiments planned for the next project period will continue to study the regulation of this inducible NO synthase in vitro and importantly will examine the role of NO in animal neuropathological models. The proposed experiments continue their investigations of the role of astrocyte-derived NO in CNS function, and will specifically examine the conditions that regulate the production of NO mRNA, protein and its activity in vitro and relate these in vitro findings to in vivo conditions in which iNOS is induced. The specific aims are to: (1) determine the various post receptor mechanisms by which inducing agents activate iNOS gene transcription, (2) investigate whether iNOS and associated enzyme activity can be regulated post-induction by receptor- activated protein kinases, and (3) to examine the expression of astrocyte iNOS mRNA in situ in selected animal neuropathological models of trauma, hyperalgesia, ischemia, and viral infection. These studies should shed light on the role of glial-derived NO in nervous system injuries.